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Castellano M, Blanco V, Li Calzi M, Costa B, Witwer K, Hill M, Cayota A, Segovia M, Tosar JP. Ribonuclease activity undermines immune sensing of naked extracellular RNA. CELL GENOMICS 2025; 5:100874. [PMID: 40334662 DOI: 10.1016/j.xgen.2025.100874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Revised: 02/26/2025] [Accepted: 04/10/2025] [Indexed: 05/09/2025]
Abstract
Cell membranes are thought of as barriers to extracellular RNA (exRNA) uptake. While naked exRNAs can be spontaneously internalized by certain cells, functional cytosolic delivery has been rarely observed. Here, we show that extracellular ribonucleases (RNases)-primarily from cell culture supplements-have obscured the study of exRNA functionality. When ribonuclease inhibitor (RI) is added to cell cultures, naked exRNAs can trigger pro-inflammatory responses in dendritic cells and macrophages, largely via endosomal Toll-like receptors (TLRs). Moreover, naked exRNAs can escape endosomes, engaging cytosolic RNA sensors. In addition, naked extracellular mRNAs can be spontaneously internalized and translated by various cell types in an RI-dependent manner. In vivo, RI co-injection amplifies naked-RNA-induced activation of splenic lymphocytes and myeloid leukocytes. Furthermore, naked RNA is inherently pro-inflammatory in RNase-poor compartments like the peritoneal cavity. These findings demonstrate that naked RNA is bioactive without requiring vesicular encapsulation, making a case for nonvesicular-exRNA-mediated intercellular communication.
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Affiliation(s)
- Mauricio Castellano
- Functional Genomics Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Immunoregulation and Inflammation Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Analytical Biochemistry Unit, School of Science, Universidad de la República, Montevideo 11400, Uruguay
| | - Valentina Blanco
- Functional Genomics Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Marco Li Calzi
- Functional Genomics Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay
| | - Bruno Costa
- Functional Genomics Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Analytical Biochemistry Unit, School of Science, Universidad de la República, Montevideo 11400, Uruguay
| | - Kenneth Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; EV Core Facility "EXCEL," Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; The Richman Family Precision Medicine Center of Excellence in Alzheimer's Disease, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Marcelo Hill
- Immunoregulation and Inflammation Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Academic Unit of Immunobiology, School of Medicine, Universidad de la República, Montevideo 11800, Uruguay
| | - Alfonso Cayota
- Functional Genomics Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Hospital de Clínicas, Universidad de la República, Montevideo 11600, Uruguay
| | - Mercedes Segovia
- Immunoregulation and Inflammation Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Academic Unit of Immunobiology, School of Medicine, Universidad de la República, Montevideo 11800, Uruguay.
| | - Juan Pablo Tosar
- Functional Genomics Laboratory, Institut Pasteur de Montevideo, Montevideo 11400, Uruguay; Analytical Biochemistry Unit, School of Science, Universidad de la República, Montevideo 11400, Uruguay.
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Li JY, Jiang RY, Wang J, Wang XJ. Advances in mRNA vaccine therapy for breast cancer research. Discov Oncol 2025; 16:673. [PMID: 40327249 PMCID: PMC12055746 DOI: 10.1007/s12672-025-02542-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025] Open
Abstract
Breast cancer represents the most prevalent cancer among women globally, constituting approximately 30% of newly diagnosed female malignancies and serving as the second leading cause of cancer-related mortality, accounting for 11.6% of deaths. Despite notable advancements in survival rates and quality of life for breast cancer patients over recent decades-achieved through interventions such as surgery, chemotherapy, radiotherapy, and endocrine therapy-there remains an urgent need for novel therapeutic strategies. This necessity arises from challenges associated with recurrence, metastasis, and drug resistance. The COVID-19 pandemic has accelerated the development of Messenger RNA (mRNA) vaccines at an unprecedented pace, and as a novel form of precision immunotherapy, mRNA vaccines are increasingly being recognized for their potential in cancer treatment. mRNA vaccines efficiently produce antigens within the cytoplasm, specifically activating the immune system to target tumor cells while minimizing the risk of T-cell tolerance. Therefore, mRNA vaccines have emerged as a promising approach in cancer immunotherapy. This review systematically examines the principles, mechanisms, advantages, key targets, and recent progress in mRNA vaccine therapy for breast cancer. Furthermore, it discusses current challenges and suggests potential directions for future research.
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Affiliation(s)
- Jia-Ying Li
- Department of Graduate Student, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Rui-Yuan Jiang
- Department of Graduate Student, Zhejiang Chinese Medical University, No. 548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China
| | - Jia Wang
- Department of Graduate Student, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China
| | - Xiao-Jia Wang
- Department of Graduate Student, Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
- Department of Medical Oncology(Breast), Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China.
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Pan M, Cao W, Zhai J, Zheng C, Xu Y, Zhang P. mRNA-based vaccines and therapies - a revolutionary approach for conquering fast-spreading infections and other clinical applications: a review. Int J Biol Macromol 2025; 309:143134. [PMID: 40233916 DOI: 10.1016/j.ijbiomac.2025.143134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/10/2025] [Accepted: 04/11/2025] [Indexed: 04/17/2025]
Abstract
Since the beginning of the COVID-19 pandemic, the development of messenger RNA (mRNA) vaccines has made significant progress in the pharmaceutical industry. The two COVID-19 mRNA vaccines from Moderna and Pfizer/BioNTech have been approved for marketing and have made significant contributions to preventing the spread of SARS-CoV-2. In addition, mRNA therapy has brought hope to some diseases that do not have specific treatment methods or are difficult to treat, such as the Zika virus and influenza virus infections, as well as the prevention and treatment of tumors. With the rapid development of in vitro transcription (IVT) technology, delivery systems, and adjuvants, mRNA therapy has also been applied to hereditary diseases such as Fabry's disease. This article reviews the recent development of mRNA vaccines for structural modification, treatment and prevention of different diseases; delivery carriers and adjuvants; and routes of administration to promote the clinical application of mRNA therapies.
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Affiliation(s)
- Mingyue Pan
- Department of Pharmacy, The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University, Shenzhen 518001, China
| | - Weiling Cao
- Department of Pharmacy, The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University, Shenzhen 518001, China
| | - Jingbo Zhai
- Key Laboratory of Zoonose Prevention and Control at Universities of Inner Mongolia Autonomous Region, Medical College, Inner Mongolia Minzu University, Tongliao 028000, China
| | - Chunfu Zheng
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, Alberta, Canada.
| | - Yingying Xu
- Department of Pharmaceutics, School of Pharmacy, Fujian Medical University, Fuzhou 350122, China.
| | - Peng Zhang
- Department of Pharmacy, The Third Affiliated Hospital (The Affiliated Luohu Hospital) of Shenzhen University, Shenzhen 518001, China.
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Jonsson A, Korsgren O, Hedin A. Transcriptomic characterization of human pancreatic CD206- and CD206 + macrophages. Sci Rep 2025; 15:12037. [PMID: 40199933 PMCID: PMC11978877 DOI: 10.1038/s41598-025-96313-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Accepted: 03/27/2025] [Indexed: 04/10/2025] Open
Abstract
Macrophages reside in all organs and participate in homeostatic- and immune regulative processes. Little is known about pancreatic macrophage gene expression. In the present study, global gene expression was characterized in human pancreatic macrophage subpopulations. CD206- and CD206 + macrophages were sorted separately from pancreatic islets and exocrine tissue to high purity using flow cytometry, followed by RNA-seq analysis. Comparing CD206- with CD206 + macrophages, CD206- showed enrichment in histones, proliferation and cell cycle regulation, glycolysis and SPP1-associated immunosuppressive polarization while CD206 + showed enrichment in complement and coagulation-, IL-10 and IL-2RA immune regulation, as well as scavenging-related gene sets. Comparing islet CD206- with exocrine CD206-, enrichments in islet samples included two sets involved in immune regulation, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Fewer differences were found between CD206 + macrophages, with enrichments in islet samples including two IL2-RA related gene sets, while enrichments in exocrine samples included sets related to extracellular matrix and immune activation. Comparing macrophages between individuals with normoglycemia, elevated HbA1c or type 2 diabetes, only a few diverse differentially expressed genes were identified. This work characterizes global gene expression and identifies differences between CD206- and CD206 + macrophage populations within the human pancreas.
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Affiliation(s)
- Alexander Jonsson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
| | - Olle Korsgren
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
- Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Anders Hedin
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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Khaddour K, Buchbinder EI. Individualized Neoantigen-Directed Melanoma Therapy. Am J Clin Dermatol 2025; 26:225-235. [PMID: 39875711 DOI: 10.1007/s40257-025-00920-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/10/2025] [Indexed: 01/30/2025]
Abstract
Individualized neoantigen-directed therapy represents a groundbreaking approach in melanoma treatment that leverages the patient's own immune system to target cancer cells. This innovative strategy involves the identification of unique immunogenic neoantigens (mutated proteins specific to an individual's tumor) and the development of therapeutic vaccines that either consist of peptide sequences or RNA encoding these neoantigens. The goal of these therapies is to induce neoantigen-specific immune responses, enabling the immune system to recognize and destroy cancer cells presenting the targeted neoantigens. This individualized approach is particularly advantageous given the genetic heterogeneity of melanoma, which exhibits distinct mutations among different patients. In contrast to traditional therapies, neoantigen-directed therapy offers a tailored treatment that potentially reduces off-target side effects and enhances therapeutic efficacy. Recent advances in neoantigen prediction and vaccine development have facilitated clinical trials exploring the combination of neoantigen vaccines with immune checkpoint inhibitors. These trials have shown promising clinical outcomes, underscoring the potential of this personalized approach. This review provides an overview of the rationale behind neoantigen-directed therapies and summarizes the current state of knowledge regarding personalized neoantigen vaccines in melanoma treatment.
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Affiliation(s)
- Karam Khaddour
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
- Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.
- Harvard Medical School, Boston, MA, 02115, USA.
| | - Elizabeth I Buchbinder
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Melanoma Disease Center, Dana-Farber Cancer Institute, Boston, MA, 02115, USA
- Harvard Medical School, Boston, MA, 02115, USA
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6
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Wang J, Cai L, Li N, Luo Z, Ren H, Zhang B, Zhao Y. Developing mRNA Nanomedicines with Advanced Targeting Functions. NANO-MICRO LETTERS 2025; 17:155. [PMID: 39979495 PMCID: PMC11842722 DOI: 10.1007/s40820-025-01665-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Accepted: 01/06/2025] [Indexed: 02/22/2025]
Abstract
The emerging messenger RNA (mRNA) nanomedicines have sprung up for disease treatment. Developing targeted mRNA nanomedicines has become a thrilling research hotspot in recent years, as they can be precisely delivered to specific organs or tissues to enhance efficiency and avoid side effects. Herein, we give a comprehensive review on the latest research progress of mRNA nanomedicines with targeting functions. mRNA and its carriers are first described in detail. Then, mechanisms of passive targeting, endogenous targeting, and active targeting are outlined, with a focus on various biological barriers that mRNA may encounter during in vivo delivery. Next, emphasis is placed on summarizing mRNA-based organ-targeting strategies. Lastly, the advantages and challenges of mRNA nanomedicines in clinical translation are mentioned. This review is expected to inspire researchers in this field and drive further development of mRNA targeting technology.
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Affiliation(s)
- Ji Wang
- Department of Radiology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, People's Republic of China
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, People's Republic of China
| | - Lijun Cai
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, People's Republic of China
| | - Ning Li
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, People's Republic of China
| | - Zhiqiang Luo
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, People's Republic of China
| | - Haozhen Ren
- Department of Radiology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, People's Republic of China.
- Department of Hepatobiliary Surgery, Hepatobiliary Institute, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, People's Republic of China.
| | - Bing Zhang
- Department of Radiology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, People's Republic of China.
| | - Yuanjin Zhao
- Department of Radiology, Nanjing Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, People's Republic of China.
- State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, People's Republic of China.
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7
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Farooq MA, Johnston APR, Trevaskis NL. Impact of nanoparticle properties on immune cell interactions in the lymph node. Acta Biomater 2025; 193:65-82. [PMID: 39701340 DOI: 10.1016/j.actbio.2024.12.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 11/21/2024] [Accepted: 12/16/2024] [Indexed: 12/21/2024]
Abstract
The lymphatic system plays an important role in health and many diseases, such as cancer, autoimmune, cardiovascular, metabolic, hepatic, viral, and other infectious diseases. The lymphatic system is, therefore, an important treatment target site for a range of diseases. Lymph nodes (LNs), rich in T cells, B cells, dendritic cells, and macrophages, are also primary sites of action for vaccines and immunotherapies. Promoting the delivery of therapeutics and vaccines to LNs can, therefore, enhance treatment efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. Several nanoparticle (NP) based delivery systems, such as polymeric NPs, lipid NPs, liposomes, micelles, and dendrimers, have been reported to enhance the delivery of therapeutics and/or vaccines to LNs. Specific uptake into the lymph following injection into tissues is highly dependent on particle properties, particularly particle size, as small molecules are more likely to be taken up by blood capillaries due to higher blood flow rates, whereas larger molecules and NPs can be specifically transported via the lymphatic vessels to LNs as the initial lymphatic capillaries are more permeable than blood capillaries. Once NPs enter LNs, particle properties also have an important influence on their disposition within the node and association with immune cells, which has significant implications for the design of vaccines and immunotherapies. This review article focuses on the impact of NP properties, such as size, surface charge and modification, and route of administration, on lymphatic uptake, retention, and interactions with immune cells in LNs. We suggest that optimizing all these factors can enhance the efficacy of vaccines or therapeutics with targets in the lymphatics and also be helpful for the rational design of vaccines. STATEMENT OF SIGNIFICANCE: The lymphatic system plays an essential role in health and is an important treatment target site for a range of diseases. Promoting the delivery of immunotherapies and vaccines to immune cells in lymph nodes can enhance efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. One of the major approaches used to deliver therapeutics and vaccines to lymph nodes is via injection in nanoparticle delivery systems. This review aims to provide an overview of the impact of nanoparticle properties, such as size, surface charge, modification, and route of administration, on lymphatic uptake, lymph node retention, and interactions with immune cells in lymph nodes. This will inform the design of future improved nanoparticle systems for vaccines and immunotherapies.
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Affiliation(s)
- Muhammad Asim Farooq
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia
| | - Angus P R Johnston
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia.
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8
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Zeng Q, Zhang S, Leng N, Xing Y. Advancing tumor vaccines: Overcoming TME challenges, delivery strategies, and biomaterial-based vaccine for enhanced immunotherapy. Crit Rev Oncol Hematol 2025; 205:104576. [PMID: 39581246 DOI: 10.1016/j.critrevonc.2024.104576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 11/03/2024] [Accepted: 11/16/2024] [Indexed: 11/26/2024] Open
Abstract
Tumor vaccines, as an immunotherapeutic approach, harness the body's immune cells to provoke antitumor responses, which have shown promising efficacy in clinical settings. However, the immunosuppressive tumor microenvironment (TME) and the ineffective vaccine delivery systems hinder the progression of many vaccines beyond phase II trials. This article begins with a comprehensive review of the complex interactions between tumor vaccines and TME, summarizing the current state of vaccine clinical research. Subsequently, we review recent advancements in targeted vaccine delivery systems and explore biomaterial-based tumor vaccines as a strategy to improve the efficacy of both delivery systems and treatment. Finally, we have presented our perspectives on tumor vaccine development, aiming to advance the field towards the creation of more effective tumor vaccines.
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Affiliation(s)
- Qingsong Zeng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Shibo Zhang
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Ning Leng
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China
| | - Yingying Xing
- School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009, PR China.
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Fayyaz A, Haqqi A, Khan R, Irfan M, Khan K, Reiner Ž, Sharifi-Rad J, Calina D. Revolutionizing cancer treatment: the rise of personalized immunotherapies. Discov Oncol 2024; 15:756. [PMID: 39692978 DOI: 10.1007/s12672-024-01638-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Accepted: 11/26/2024] [Indexed: 12/19/2024] Open
Abstract
Interest in biological therapy for cancer has surged due to its precise targeting of cancer cells and minimized impact on surrounding healthy tissues. This review discusses various biological cancer therapies, highlighting advanced alternatives over conventional chemotherapy alone. It explores DNA and RNA-based vaccines, T-cell modifications, adoptive cell transfer, CAR T cell therapy, angiogenesis inhibitors, and the combination of immunotherapy with chemotherapy, offering a holistic view of the potential in cancer treatment. Additionally, it discusses the role of nanotechnology in increasing the efficacy of cancer-targeting drugs, as well as cytokine and immunoconjugate therapies for bolstering immune system effectiveness against neoplastic cells. The potential of gene potential for precise targeting of cancer-linked genes and the application of oncolytic viruses against virus-associated cancers are also discussed. The review identifies significant advancements in the targeted treatment of cancer by biological methods. It acknowledges the challenges, including drug resistance and the need for high specificity in certain therapies, while also highlighting the effectiveness of cancer vaccines, modified T-cells, and oncolytic viruses. Biological therapies are a promising frontier in cancer treatment, offering the potential for more personalized and effective therapeutic strategies. Despite existing challenges, ongoing research and clinical trials are fundamental for overcoming current limitations and enhancing the efficacy of biological therapies in cancer care.
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Affiliation(s)
- Amna Fayyaz
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Aleena Haqqi
- School of Medical Laboratory Technology, Faculty of Allied Health Sciences, Minhaj University Lahore (MUL), Lahore, 54000, Pakistan
| | - Rashid Khan
- Department of Pharmacy, Punjab University College of Pharmacy University of Punjab Lahore, Lahore, 54000, Pakistan
| | - Muhammad Irfan
- Atta-Ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad, Pakistan
| | - Khushbukhat Khan
- Cancer Clinical Research Unit, Trials360, Lahore, 54000, Pakistan.
| | - Željko Reiner
- Department for Metabolic Diseases, University Hospital Center Zagreb, Zagreb, Croatia
- Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Javad Sharifi-Rad
- Universidad Espíritu Santo, Samborondón, 092301, Ecuador.
- Centro de Estudios Tecnológicos, Universitarios del Golfo, Veracruz, Mexico.
- Department of Medicine, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
| | - Daniela Calina
- Department of Clinical Pharmacy, University of Medicine and Pharmacy of Craiova, 200349, Craiova, Romania.
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Shariati A, Khani P, Nasri F, Afkhami H, Khezrpour A, Kamrani S, Shariati F, Alavimanesh S, Modarressi MH. mRNA cancer vaccines from bench to bedside: a new era in cancer immunotherapy. Biomark Res 2024; 12:157. [PMID: 39696625 DOI: 10.1186/s40364-024-00692-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 11/15/2024] [Indexed: 12/20/2024] Open
Abstract
Harnessing the power of the immune system to target cancer cells is one of the most appealing approaches for cancer therapy. Among these immunotherapies, messenger ribonucleic acid (mRNA) cancer vaccines are worthy of consideration, as they have demonstrated promising results in clinical trials. These vaccines have proven to be safe and well-tolerated. They can be easily mass-produced in a relatively short time and induce a systemic immune response effective against both the primary tumor and metastases. Transcripts encoding immunomodulatory molecules can also be incorporated into the mRNA, enhancing its efficacy. On the other hand, there are some challenges associated with their application, including mRNA instability, insufficient uptake by immune cells, and intrinsic immunogenicity, which can block mRNA translation. Many innovations have been suggested to overcome these obstacles, including structural modification (such as 5' cap modification), optimizing delivery vehicles (especially dendritic cells (DCs) and nanoparticles), and using antigens that can enhance immunogenicity by circumventing tolerance mechanisms. A popular approach is to combine mRNA cancer vaccines with traditional and novel cancer treatments like chemotherapy, radiotherapy, and immune checkpoint blockade (ICB). They are most efficacious when combined with other therapies like ICBs. There is still a long way to go before these vaccines enter the standard of care for cancer patients, but with the incredible pace of development in this field, their clinical application will soon be witnessed. This review highlights the recent advances and challenges of mRNA cancer vaccines. Finally, some of the most prominent clinical applications of these vaccines will be reviewed.
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Affiliation(s)
- Alireza Shariati
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Pouria Khani
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Farzad Nasri
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hamed Afkhami
- Cellular and Molecular Research Center, Qom University of Medical Sciences, Qom, Iran
- Nervous System Stem Cells Research Center, Semnan University of Medical Sciences, Semnan, Iran
- Department of Medical Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
| | - Arya Khezrpour
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Sina Kamrani
- Department of Orthopedic, Faculty of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Fatemeh Shariati
- Department of Genetics, North Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Sajad Alavimanesh
- Student Research Committee, Shahrekord University of Medical Sciences, Shahrekord, Iran.
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran.
| | - Mohammad Hossein Modarressi
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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Haghighi E, Abolmaali SS, Dehshahri A, Mousavi Shaegh SA, Azarpira N, Tamaddon AM. Navigating the intricate in-vivo journey of lipid nanoparticles tailored for the targeted delivery of RNA therapeutics: a quality-by-design approach. J Nanobiotechnology 2024; 22:710. [PMID: 39543630 PMCID: PMC11566655 DOI: 10.1186/s12951-024-02972-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 11/03/2024] [Indexed: 11/17/2024] Open
Abstract
RNA therapeutics, such as mRNA, siRNA, and CRISPR-Cas9, present exciting avenues for treating diverse diseases. However, their potential is commonly hindered by vulnerability to degradation and poor cellular uptake, requiring effective delivery systems. Lipid nanoparticles (LNPs) have emerged as a leading choice for in vivo RNA delivery, offering protection against degradation, enhanced cellular uptake, and facilitation of endosomal escape. However, LNPs encounter numerous challenges for targeted RNA delivery in vivo, demanding advanced particle engineering, surface functionalization with targeting ligands, and a profound comprehension of the biological milieu in which they function. This review explores the structural and physicochemical characteristics of LNPs, in-vivo fate, and customization for RNA therapeutics. We highlight the quality-by-design (QbD) approach for targeted delivery beyond the liver, focusing on biodistribution, immunogenicity, and toxicity. In addition, we explored the current challenges and strategies associated with LNPs for in-vivo RNA delivery, such as ensuring repeated-dose efficacy, safety, and tissue-specific gene delivery. Furthermore, we provide insights into the current clinical applications in various classes of diseases and finally prospects of LNPs in RNA therapeutics.
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Affiliation(s)
- Elahe Haghighi
- Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Samira Sadat Abolmaali
- Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, Iran.
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Ali Dehshahri
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Pharmaceutical Biotechnology, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Ali Mousavi Shaegh
- Laboratory of Microfluidics and Medical Microsystems, Research Institute for Medical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
- Orthopedic Research Center, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
- Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Negar Azarpira
- Stem Cells Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Mohammad Tamaddon
- Department of Pharmaceutical Nanotechnology, Shiraz University of Medical Sciences, Shiraz, Iran.
- Center for Nanotechnology in Drug Delivery, Shiraz University of Medical Sciences, Shiraz, Iran.
- Department of Pharmaceutics, Shiraz University of Medical Sciences, Shiraz, Iran.
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12
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Karimi-Sani I, Molavi Z, Naderi S, Mirmajidi SH, Zare I, Naeimzadeh Y, Mansouri A, Tajbakhsh A, Savardashtaki A, Sahebkar A. Personalized mRNA vaccines in glioblastoma therapy: from rational design to clinical trials. J Nanobiotechnology 2024; 22:601. [PMID: 39367418 PMCID: PMC11453023 DOI: 10.1186/s12951-024-02882-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 09/26/2024] [Indexed: 10/06/2024] Open
Abstract
Glioblastomas (GBMs) are the most common and aggressive malignant brain tumors, presenting significant challenges for treatment due to their invasive nature and localization in critical brain regions. Standard treatment includes surgical resection followed by radiation and adjuvant chemotherapy with temozolomide (TMZ). Recent advances in immunotherapy, including the use of mRNA vaccines, offer promising alternatives. This review focuses on the emerging use of mRNA vaccines for GBM treatment. We summarize recent advancements, evaluate current obstacles, and discuss notable successes in this field. Our analysis highlights that while mRNA vaccines have shown potential, their use in GBM treatment is still experimental. Ongoing research and clinical trials are essential to fully understand their therapeutic potential. Future developments in mRNA vaccine technology and insights into GBM-specific immune responses may lead to more targeted and effective treatments. Despite the promise, further research is crucial to validate and optimize the effectiveness of mRNA vaccines in combating GBM.
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Affiliation(s)
- Iman Karimi-Sani
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Molavi
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Samaneh Naderi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyedeh-Habibeh Mirmajidi
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iman Zare
- Research and Development Department, Sina Medical Biochemistry Technologies Co. Ltd., Shiraz, 7178795844, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Atena Mansouri
- Cellular and Molecular Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Amir Tajbakhsh
- Pharmaceutical Sciences Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Department of Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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13
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Kohli AS, Sanyal S, Kaushal RS, Dwivedi M. An Insight into Immunological Therapeutic Approach against Cancer: Potential Anti-cancer Vaccines. Curr Genomics 2024; 26:175-190. [PMID: 40433416 PMCID: PMC12105320 DOI: 10.2174/0113892029319505240821063238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/08/2024] [Accepted: 07/31/2024] [Indexed: 05/29/2025] Open
Abstract
The development of a cancer vaccine comes with its complications and designing and developing a vaccine against foreign invaders such as bacterial and viral particles is not as complex and multi-faceted as the preparation of immunotherapy for host-infected cells which resemble our own body cells. The entire research and development framework of designing a vaccine for cancerous cells lies entirely on the remarkable aspect of notifying specific interactions and acclimatising the immune system. This review aims to compile the several fronts research-based methodology applies to in terms of developing a therapeutic, preventive or personalised vaccine for cancer. The approach lays focus on the identification and selection of targets for vaccine development which have come to light as immune biomarkers. Furthemore, significant aspects of personalised and precision vaccines and the fine line that runs between these approaches have also been discussed.
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Affiliation(s)
- Arjun Singh Kohli
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Ext., Lucknow, 226028, India
| | - Somali Sanyal
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Ext., Lucknow, 226028, India
| | | | - Manish Dwivedi
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Gomtinagar Ext., Lucknow, 226028, India
- Research Cell, Amity University Uttar Pradesh, Lucknow Campus, India
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14
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Li M, Xie Y, Zhang J, Zhou X, Gao L, He M, Liu X, Miao X, Liu Y, Cao R, Jia Y, Zeng Z, Liu L. Intratumoral injection of mRNA encoding survivin in combination with STAT3 inhibitor stattic enhances antitumor effects. Cancer Lett 2024; 598:217111. [PMID: 38972347 DOI: 10.1016/j.canlet.2024.217111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 07/04/2024] [Indexed: 07/09/2024]
Abstract
Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.
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Affiliation(s)
- Min Li
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Ying Xie
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Jincheng Zhang
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Xue Zhou
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Lei Gao
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Mengmeng He
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Xianmei Liu
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Xinyi Miao
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Yu Liu
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Rong Cao
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China
| | - Yi Jia
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Health Medicine Biotechnology of Institution of Higher Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China.
| | - Zhu Zeng
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Health Medicine Biotechnology of Institution of Higher Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China.
| | - Lina Liu
- Engineering Research Center of Cellular Immunotherapy of Guizhou Province, Key Laboratory of Infectious Immune and Antibody Engineering of Guizhou Province, School of Basic Medical Science/School of Biology and Engineering (School of Health Medicine Modern Industry), Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Guizhou Medical University, Guiyang, Guizhou, China; Key Laboratory of Biological and Medical Engineering/Immune Cells and Antibody Engineering Research Center of Guizhou Province/Engineering Research Center of Health Medicine Biotechnology of Institution of Higher Education of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou, China.
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15
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Uher O, Hadrava Vanova K, Taïeb D, Calsina B, Robledo M, Clifton-Bligh R, Pacak K. The Immune Landscape of Pheochromocytoma and Paraganglioma: Current Advances and Perspectives. Endocr Rev 2024; 45:521-552. [PMID: 38377172 PMCID: PMC11244254 DOI: 10.1210/endrev/bnae005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 12/19/2023] [Accepted: 02/02/2024] [Indexed: 02/22/2024]
Abstract
Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors derived from neural crest cells from adrenal medullary chromaffin tissues and extra-adrenal paraganglia, respectively. Although the current treatment for PPGLs is surgery, optimal treatment options for advanced and metastatic cases have been limited. Hence, understanding the role of the immune system in PPGL tumorigenesis can provide essential knowledge for the development of better therapeutic and tumor management strategies, especially for those with advanced and metastatic PPGLs. The first part of this review outlines the fundamental principles of the immune system and tumor microenvironment, and their role in cancer immunoediting, particularly emphasizing PPGLs. We focus on how the unique pathophysiology of PPGLs, such as their high molecular, biochemical, and imaging heterogeneity and production of several oncometabolites, creates a tumor-specific microenvironment and immunologically "cold" tumors. Thereafter, we discuss recently published studies related to the reclustering of PPGLs based on their immune signature. The second part of this review discusses future perspectives in PPGL management, including immunodiagnostic and promising immunotherapeutic approaches for converting "cold" tumors into immunologically active or "hot" tumors known for their better immunotherapy response and patient outcomes. Special emphasis is placed on potent immune-related imaging strategies and immune signatures that could be used for the reclassification, prognostication, and management of these tumors to improve patient care and prognosis. Furthermore, we introduce currently available immunotherapies and their possible combinations with other available therapies as an emerging treatment for PPGLs that targets hostile tumor environments.
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Affiliation(s)
- Ondrej Uher
- Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA
| | - Katerina Hadrava Vanova
- Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA
| | - David Taïeb
- Department of Nuclear Medicine, CHU de La Timone, Marseille 13005, France
| | - Bruna Calsina
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
- Familiar Cancer Clinical Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid 28029, Spain
| | - Roderick Clifton-Bligh
- Department of Endocrinology, Royal North Shore Hospital, Sydney 2065, NSW, Australia
- Cancer Genetics Laboratory, Kolling Institute, University of Sydney, Sydney 2065, NSW, Australia
| | - Karel Pacak
- Section of Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1109, USA
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16
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Guasp P, Reiche C, Sethna Z, Balachandran VP. RNA vaccines for cancer: Principles to practice. Cancer Cell 2024; 42:1163-1184. [PMID: 38848720 DOI: 10.1016/j.ccell.2024.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Revised: 04/29/2024] [Accepted: 05/06/2024] [Indexed: 06/09/2024]
Abstract
Vaccines are the most impactful medicines to improve health. Though potent against pathogens, vaccines for cancer remain an unfulfilled promise. However, recent advances in RNA technology coupled with scientific and clinical breakthroughs have spurred rapid discovery and potent delivery of tumor antigens at speed and scale, transforming cancer vaccines into a tantalizing prospect. Yet, despite being at a pivotal juncture, with several randomized clinical trials maturing in upcoming years, several critical questions remain: which antigens, tumors, platforms, and hosts can trigger potent immunity with clinical impact? Here, we address these questions with a principled framework of cancer vaccination from antigen detection to delivery. With this framework, we outline features of emergent RNA technology that enable rapid, robust, real-time vaccination with somatic mutation-derived neoantigens-an emerging "ideal" antigen class-and highlight latent features that have sparked the belief that RNA could realize the enduring vision for vaccines against cancer.
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Affiliation(s)
- Pablo Guasp
- Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Charlotte Reiche
- Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zachary Sethna
- Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Vinod P Balachandran
- Immuno-Oncology Service, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Hepatopancreatobiliary Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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17
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Salomon N, Helm A, Selmi A, Fournier C, Diken M, Schrörs B, Scholz M, Kreiter S, Durante M, Vascotto F. Carbon Ion and Photon Radiation Therapy Show Enhanced Antitumoral Therapeutic Efficacy With Neoantigen RNA-LPX Vaccines in Preclinical Colon Carcinoma Models. Int J Radiat Oncol Biol Phys 2024; 119:936-945. [PMID: 38163521 DOI: 10.1016/j.ijrobp.2023.12.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 12/07/2023] [Accepted: 12/27/2023] [Indexed: 01/03/2024]
Abstract
PURPOSE Personalized liposome-formulated mRNA vaccines (RNA-LPX) are a powerful new tool in cancer immunotherapy. In preclinical tumor models, RNA-LPX vaccines are known to achieve potent results when combined with conventional X-ray radiation therapy (XRT). Densely ionizing radiation used in carbon ion radiation therapy (CIRT) may induce distinct effects in combination with immunotherapy compared with sparsely ionizing X-rays. METHODS AND MATERIALS Within this study, we investigate the potential of CIRT and isoeffective doses of XRT to mediate tumor growth inhibition and survival in murine colon adenocarcinoma models in conjunction with neoantigen (neoAg)-specific RNA-LPX vaccines encoding both major histocompatibility complex (MHC) class I- and class II-restricted tumor-specific neoantigens. We characterize tumor immune infiltrates and antigen-specific T cell responses by flow cytometry and interferon-γ enzyme-linked immunosorbent spot (ELISpot) analyses, respectively. RESULTS NeoAg RNA-LPX vaccines significantly potentiate radiation therapy-mediated tumor growth inhibition. CIRT and XRT alone marginally prime neoAg-specific T cell responses detected in the tumors but not in the blood or spleens of mice. Infiltration and cytotoxicity of neoAg-specific T cells is strongly driven by RNA-LPX vaccines and is accompanied by reduced expression of the inhibitory markers PD-1 and Tim-3 on these cells. The neoAg RNA-LPX vaccine shows similar overall therapeutic efficacy in combination with both CIRT and XRT, even if the physical radiation dose is lower for carbon ions than for X-rays. CONCLUSIONS We hence conclude that the combination of CIRT and neoAg RNA-LPX vaccines is a promising strategy for the treatment of radioresistant tumors.
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Affiliation(s)
- Nadja Salomon
- TRON gGmbH, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
| | - Alexander Helm
- GSI Helmholtzzentrum for Heavy Ion Research GmbH, Darmstadt, Germany
| | - Abderaouf Selmi
- TRON gGmbH, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Claudia Fournier
- GSI Helmholtzzentrum for Heavy Ion Research GmbH, Darmstadt, Germany
| | - Mustafa Diken
- TRON gGmbH, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Barbara Schrörs
- TRON gGmbH, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Michael Scholz
- GSI Helmholtzzentrum for Heavy Ion Research GmbH, Darmstadt, Germany
| | - Sebastian Kreiter
- TRON gGmbH, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marco Durante
- GSI Helmholtzzentrum for Heavy Ion Research GmbH, Darmstadt, Germany; Technical University Darmstadt, Institute of Condensed Matter Physics, Darmstadt, Germany; University Federico II, Department of Physics "Ettore Pancini", Naples, Italy
| | - Fulvia Vascotto
- TRON gGmbH, Translational Oncology at the University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
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18
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Parveen A, Elkordy AA. Brief Insights into mRNA Vaccines: Their Successful Production and Nanoformulation for Effective Response against COVID-19 and Their Potential Success for Influenza A and B. Pathogens 2024; 13:500. [PMID: 38921798 PMCID: PMC11206352 DOI: 10.3390/pathogens13060500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 06/27/2024] Open
Abstract
A mRNA vaccine is a type of vaccine that induces an immune response. Antigen-encoding mRNA is delivered via vaccine carriers into the immune cells, which are produced because of antigen-encoding mRNA translation, a protein. For example, COVID-19 mRNA vaccines produce the spike protein of the COVID-19 virus, whereas for influenza virus, mRNA vaccines target the haemagglutinin protein to treat the flu, and it requires modifications depending on the pandemic or seasonal viruses as it is capable of adapting the immune response, which makes the development of vaccines arduous. The protein molecule promotes an adaptive immune response that eliminates and terminates the corresponding virus or pathogen. There are many challenges to delivering an mRNA vaccine into the body; hence, the encapsulation of the mRNA (usually within lipid nanoparticles) is necessary to protect the mRNA from the body's surrounding environment. In this review article, we focus mainly on the production, formulation, and stabilization of mRNA vaccines in general, elaborating more on and focusing more on SARS-CoV-2, or COVID-19, and influenza viruses, which have become a major concern as these viruses have turned into life-threatening diseases.
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Affiliation(s)
| | - Amal Ali Elkordy
- School of Pharmacy and Pharmaceutical Sciences, Faculty of Health Sciences and Wellbeing, University of Sunderland, Sunderland SR1 3SD, UK;
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19
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Amaya L, Abe B, Liu J, Zhao F, Zhang WL, Chen R, Li R, Wang S, Kamber RA, Tsai MC, Bassik MC, Majeti R, Chang HY. Pathways for macrophage uptake of cell-free circular RNAs. Mol Cell 2024; 84:2104-2118.e6. [PMID: 38761795 PMCID: PMC11218042 DOI: 10.1016/j.molcel.2024.04.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 03/04/2024] [Accepted: 04/26/2024] [Indexed: 05/20/2024]
Abstract
Circular RNAs (circRNAs) are stable RNAs present in cell-free RNA, which may comprise cellular debris and pathogen genomes. Here, we investigate the phenomenon and mechanism of cellular uptake and intracellular fate of exogenous circRNAs. Human myeloid cells and B cells selectively internalize extracellular circRNAs. Macrophage uptake of circRNA is rapid, energy dependent, and saturable. CircRNA uptake can lead to translation of encoded sequences and antigen presentation. The route of internalization influences immune activation after circRNA uptake, with distinct gene expression programs depending on the route of RNA delivery. Genome-scale CRISPR screens and chemical inhibitor studies nominate macrophage scavenger receptor MSR1, Toll-like receptors, and mTOR signaling as key regulators of receptor-mediated phagocytosis of circRNAs, a dominant pathway to internalize circRNAs in parallel to macropinocytosis. These results suggest that cell-free circRNA serves as an "eat me" signal and danger-associated molecular pattern, indicating orderly pathways of recognition and disposal.
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Affiliation(s)
- Laura Amaya
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Brian Abe
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA 94305, USA
| | - Jie Liu
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Feifei Zhao
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Wenyan Lucy Zhang
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Robert Chen
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA
| | - Rui Li
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA
| | - Steven Wang
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Roarke A Kamber
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Miao-Chih Tsai
- RNA Medicine Program, Stanford University, Stanford, CA 94305, USA
| | - Michael C Bassik
- Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Ravindra Majeti
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Howard Y Chang
- Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; RNA Medicine Program, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
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20
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Mendez-Gomez HR, DeVries A, Castillo P, von Roemeling C, Qdaisat S, Stover BD, Xie C, Weidert F, Zhao C, Moor R, Liu R, Soni D, Ogando-Rivas E, Chardon-Robles J, McGuiness J, Zhang D, Chung MC, Marconi C, Michel S, Barpujari A, Jobin GW, Thomas N, Ma X, Campaneria Y, Grippin A, Karachi A, Li D, Sahay B, Elliott L, Foster TP, Coleman KE, Milner RJ, Sawyer WG, Ligon JA, Simon E, Cleaver B, Wynne K, Hodik M, Molinaro AM, Guan J, Kellish P, Doty A, Lee JH, Massini T, Kresak JL, Huang J, Hwang EI, Kline C, Carrera-Justiz S, Rahman M, Gatica S, Mueller S, Prados M, Ghiaseddin AP, Silver NL, Mitchell DA, Sayour EJ. RNA aggregates harness the danger response for potent cancer immunotherapy. Cell 2024; 187:2521-2535.e21. [PMID: 38697107 PMCID: PMC11767857 DOI: 10.1016/j.cell.2024.04.003] [Citation(s) in RCA: 46] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 01/09/2024] [Accepted: 04/03/2024] [Indexed: 05/04/2024]
Abstract
Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
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Affiliation(s)
- Hector R Mendez-Gomez
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Anna DeVries
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Paul Castillo
- University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Christina von Roemeling
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Sadeem Qdaisat
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA; University of Florida Genetics Institute, Gainesville, FL 32610, USA
| | - Brian D Stover
- University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Chao Xie
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Frances Weidert
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Chong Zhao
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Rachel Moor
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Ruixuan Liu
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Dhruvkumar Soni
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Elizabeth Ogando-Rivas
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Jonathan Chardon-Robles
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - James McGuiness
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Dingpeng Zhang
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Michael C Chung
- University of Texas at Austin, College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Austin TX 78712
| | - Christiano Marconi
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Stephen Michel
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Arnav Barpujari
- University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Gabriel W Jobin
- University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Nagheme Thomas
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Xiaojie Ma
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA; University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Yodarlynis Campaneria
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Adam Grippin
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Aida Karachi
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Derek Li
- University of Florida, Division of Quantitative Sciences, UF Health Cancer Center, Gainesville, FL 32610, USA
| | - Bikash Sahay
- University of Florida, College of Veterinary Medicine, Gainesville, FL 32610, USA
| | - Leighton Elliott
- University of Florida, Department of Medicine, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Timothy P Foster
- University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Kirsten E Coleman
- University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Rowan J Milner
- University of Florida, College of Veterinary Medicine, Gainesville, FL 32610, USA
| | - W Gregory Sawyer
- H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - John A Ligon
- University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA
| | - Eugenio Simon
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Brian Cleaver
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Kristine Wynne
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Marcia Hodik
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Annette M Molinaro
- University of California, San Francisco, Department of Neurological Surgery, San Francisco, CA 94158, USA
| | - Juan Guan
- University of Texas at Austin, College of Pharmacy, Division of Chemical Biology and Medicinal Chemistry, Austin TX 78712
| | - Patrick Kellish
- University of Florida Interdisciplinary Center for Biotechnology Research, Gainesville, FL 32610, USA
| | - Andria Doty
- University of Florida Interdisciplinary Center for Biotechnology Research, Gainesville, FL 32610, USA
| | - Ji-Hyun Lee
- University of Florida, Department of Biostatistics, Gainesville, FL 32610, USA
| | - Tara Massini
- University of Florida, Department of Radiology, Gainesville, FL 32610, USA
| | - Jesse L Kresak
- University of Florida, Department of Pathology, Gainesville, FL 32610, USA
| | - Jianping Huang
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Eugene I Hwang
- Children's National Hospital, Center for Cancer and Blood Disorders, Washington, DC 20010, USA
| | - Cassie Kline
- University of Pennsylvania Perelman School of Medicine, Children's Hospital of Philadelphia, Department of Pediatrics, Division of Oncology, Philadelphia, PA 19104, USA
| | | | - Maryam Rahman
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Sebastian Gatica
- University of Florida, Department of Anesthesiology, Gainesville, FL 32610, USA
| | - Sabine Mueller
- University of California, San Francisco, Department of Neurology, Neurological Surgery, and Pediatrics, San Francisco, CA 94158, USA
| | - Michael Prados
- University of California, San Francisco, Department of Neurological Surgery, San Francisco, CA 94158, USA
| | - Ashley P Ghiaseddin
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Natalie L Silver
- Cleveland Clinic, Center of Immunotherapy and Precision Immuno-Oncology/Head and Neck Institute, Cleveland, OH 44106, USA
| | - Duane A Mitchell
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA
| | - Elias J Sayour
- University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA; University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA.
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21
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Abbasi S, Matsui-Masai M, Yasui F, Hayashi A, Tockary TA, Mochida Y, Akinaga S, Kohara M, Kataoka K, Uchida S. Carrier-free mRNA vaccine induces robust immunity against SARS-CoV-2 in mice and non-human primates without systemic reactogenicity. Mol Ther 2024; 32:1266-1283. [PMID: 38569556 PMCID: PMC11081875 DOI: 10.1016/j.ymthe.2024.03.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2023] [Revised: 02/21/2024] [Accepted: 03/11/2024] [Indexed: 04/05/2024] Open
Abstract
Carrier-free naked mRNA vaccines may reduce the reactogenicity associated with delivery carriers; however, their effectiveness against infectious diseases has been suboptimal. To boost efficacy, we targeted the skin layer rich in antigen-presenting cells (APCs) and utilized a jet injector. The jet injection efficiently introduced naked mRNA into skin cells, including APCs in mice. Further analyses indicated that APCs, after taking up antigen mRNA in the skin, migrated to the lymph nodes (LNs) for antigen presentation. Additionally, the jet injection provoked localized lymphocyte infiltration in the skin, serving as a physical adjuvant for vaccination. Without a delivery carrier, our approach confined mRNA distribution to the injection site, preventing systemic mRNA leakage and associated systemic proinflammatory reactions. In mouse vaccination, the naked mRNA jet injection elicited robust antigen-specific antibody production over 6 months, along with germinal center formation in LNs and the induction of both CD4- and CD8-positive T cells. By targeting the SARS-CoV-2 spike protein, this approach provided protection against viral challenge. Furthermore, our approach generated neutralizing antibodies against SARS-CoV-2 in non-human primates at levels comparable to those observed in mice. In conclusion, our approach offers a safe and effective option for mRNA vaccines targeting infectious diseases.
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Affiliation(s)
- Saed Abbasi
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Miki Matsui-Masai
- Department of Research, NANO MRNA Co., Ltd., 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Fumihiko Yasui
- Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
| | - Akimasa Hayashi
- Department of Pathology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan
| | - Theofilus A Tockary
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Yuki Mochida
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan; Department of Advanced Nanomedical Engineering, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
| | - Shiro Akinaga
- Department of Research, NANO MRNA Co., Ltd., 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan
| | - Michinori Kohara
- Department of Microbiology and Cell Biology, Tokyo Metropolitan Institute of Medical Science, 2-1-6, Kamikitazawa, Setagaya-ku, Tokyo 156-8506, Japan
| | - Kazunori Kataoka
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan.
| | - Satoshi Uchida
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki 210-0821, Japan; Department of Advanced Nanomedical Engineering, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
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22
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Castellano M, Blanco V, Calzi ML, Costa B, Witwer K, Hill M, Cayota A, Segovia M, Tosar JP. Ribonuclease activity undermines immune sensing of naked extracellular RNA. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.23.590771. [PMID: 38712104 PMCID: PMC11071435 DOI: 10.1101/2024.04.23.590771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
The plasma membrane and the membrane of endosomal vesicles are considered physical barriers preventing extracellular RNA uptake. While naked RNA can be spontaneously internalized by certain cells types, functional delivery of naked RNA into the cytosol has been rarely observed. Here we show that extracellular ribonucleases, mainly derived from cell culture supplements, have so far hindered the study of extracellular RNA functionality. In the presence of active ribonuclease inhibitors (RI), naked bacterial RNA is pro-inflammatory when spiked in the media of dendritic cells and macrophages. In murine cells, this response mainly depends on the action of endosomal Toll-like receptors. However, we also show that naked RNA can perform endosomal escape and engage with cytosolic RNA sensors and ribosomes. For example, naked mRNAs encoding reporter proteins can be spontaneously internalized and translated by a variety of cell types, in an RI-dependent manner. In vivo, RI co-injection enhances the activation induced by naked extracellular RNA on splenic lymphocytes and myeloid-derived leukocytes. Furthermore, naked extracellular RNA is inherently pro-inflammatory in ribonuclease-poor compartments such as the peritoneal cavity. Overall, these results demonstrate that naked RNA is bioactive and does not need encapsulation inside synthetic or biological lipid vesicles for functional uptake, making a case for nonvesicular extracellular RNA-mediated intercellular communication.
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Affiliation(s)
- Mauricio Castellano
- Functional Genomics Laboratory, Institut Pasteur Montevideo, Uruguay
- Immunoregulation and Inflammation Laboratory, Institut Pasteur Montevideo, Uruguay
| | - Valentina Blanco
- Functional Genomics Laboratory, Institut Pasteur Montevideo, Uruguay
| | - Marco Li Calzi
- Functional Genomics Laboratory, Institut Pasteur Montevideo, Uruguay
| | - Bruno Costa
- Functional Genomics Laboratory, Institut Pasteur Montevideo, Uruguay
- Analytical Biochemistry Unit, School of Science, Universidad de la República, Uruguay
| | - Kenneth Witwer
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- EV Core Facility “EXCEL”, Institute for Basic Biomedical Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
- The Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Marcelo Hill
- Immunoregulation and Inflammation Laboratory, Institut Pasteur Montevideo, Uruguay
- Academic Unit of Immunobiology, School of Medicine, Universidad de la República, Uruguay
| | - Alfonso Cayota
- Functional Genomics Laboratory, Institut Pasteur Montevideo, Uruguay
- Hospital de Clínicas, Universidad de la República, Uruguay
| | - Mercedes Segovia
- Immunoregulation and Inflammation Laboratory, Institut Pasteur Montevideo, Uruguay
- Academic Unit of Immunobiology, School of Medicine, Universidad de la República, Uruguay
| | - Juan Pablo Tosar
- Functional Genomics Laboratory, Institut Pasteur Montevideo, Uruguay
- Analytical Biochemistry Unit, School of Science, Universidad de la República, Uruguay
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23
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Kim J, Eygeris Y, Ryals RC, Jozić A, Sahay G. Strategies for non-viral vectors targeting organs beyond the liver. NATURE NANOTECHNOLOGY 2024; 19:428-447. [PMID: 38151642 DOI: 10.1038/s41565-023-01563-4] [Citation(s) in RCA: 40] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 11/01/2023] [Indexed: 12/29/2023]
Abstract
In recent years, nanoparticles have evolved to a clinical modality to deliver diverse nucleic acids. Rising interest in nanomedicines comes from proven safety and efficacy profiles established by continuous efforts to optimize physicochemical properties and endosomal escape. However, despite their transformative impact on the pharmaceutical industry, the clinical use of non-viral nucleic acid delivery is limited to hepatic diseases and vaccines due to liver accumulation. Overcoming liver tropism of nanoparticles is vital to meet clinical needs in other organs. Understanding the anatomical structure and physiological features of various organs would help to identify potential strategies for fine-tuning nanoparticle characteristics. In this Review, we discuss the source of liver tropism of non-viral vectors, present a brief overview of biological structure, processes and barriers in select organs, highlight approaches available to reach non-liver targets, and discuss techniques to accelerate the discovery of non-hepatic therapies.
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Affiliation(s)
- Jeonghwan Kim
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, USA
- College of Pharmacy, Yeungnam University, Gyeongsan, South Korea
| | - Yulia Eygeris
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, USA
| | - Renee C Ryals
- Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA
| | - Antony Jozić
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, USA
| | - Gaurav Sahay
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Portland, OR, USA.
- Department of Ophthalmology, Casey Eye Institute, Oregon Health and Science University, Portland, OR, USA.
- Department of Biomedical Engineering, Robertson Life Sciences Building, Oregon Health and Science University, Portland, OR, USA.
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24
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Wang J, Zhu H, Gan J, Liang G, Li L, Zhao Y. Engineered mRNA Delivery Systems for Biomedical Applications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2308029. [PMID: 37805865 DOI: 10.1002/adma.202308029] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/05/2023] [Indexed: 10/09/2023]
Abstract
Messenger RNA (mRNA)-based therapeutic strategies have shown remarkable promise in preventing and treating a staggering range of diseases. Optimizing the structure and delivery system of engineered mRNA has greatly improved its stability, immunogenicity, and protein expression levels, which has led to a wider range of uses for mRNA therapeutics. Herein, a thorough analysis of the optimization strategies used in the structure of mRNA is first provided and delivery systems are described in great detail. Furthermore, the latest advancements in biomedical engineering for mRNA technology, including its applications in combatting infectious diseases, treating cancer, providing protein replacement therapy, conducting gene editing, and more, are summarized. Lastly, a perspective on forthcoming challenges and prospects concerning the advancement of mRNA therapeutics is offered. Despite these challenges, mRNA-based therapeutics remain promising, with the potential to revolutionize disease treatment and contribute to significant advancements in the biomedical field.
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Affiliation(s)
- Ji Wang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Haofang Zhu
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Jingjing Gan
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Gaofeng Liang
- Institute of Organoids on Chips Translational Research, Henan Academy of Sciences, Zhengzhou, 450009, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China
| | - Yuanjin Zhao
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
- Institute of Organoids on Chips Translational Research, Henan Academy of Sciences, Zhengzhou, 450009, China
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25
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Josi R, Ogrina A, Rothen D, Balke I, Casaramona AS, de Brot S, Mohsen MO. Intranodal Injection of Immune Activator Demonstrates Antitumor Efficacy in an Adjuvant Approach. Vaccines (Basel) 2024; 12:355. [PMID: 38675737 PMCID: PMC11054762 DOI: 10.3390/vaccines12040355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Revised: 03/14/2024] [Accepted: 03/19/2024] [Indexed: 04/28/2024] Open
Abstract
The tumor-draining lymph nodes (tdLN) are the initial site of metastases and are the prime site for generating robust antitumor responses. In this study, we explored the efficacy of a universal immune activator (ImmAct) targeted to the tdLN. This approach can be viewed as an attempt to turn a cold, unresponsive tdLN into a hot, responsive site. The adjuvant antitumor efficacy of our novel intranodal injection was evaluated in an aggressive metastatic mammary carcinoma murine model. The cancer cells were inoculated subcutaneously in the lower quadrant of the mouse to provoke the tdLN (inguinal lymph node). The study encompasses a range of methodologies, including in vivo and in vitro assays and high-dimensional flow cytometry analysis. Our findings demonstrated that intranodal administration of ImmAct following the dissection of the primary tumor led to improved tumor-free survival and minimized weight loss. ImmAct led to both local and systemic alterations in the cellular and humoral immunity. Additionally, after ImmAct treatment, non-responders showed a higher rate of exhausted CD8+ T cells compared to responders. Indeed, our innovative approach surpassed the gold standard surgery of sentinel lymph node excision. Overall, intranodal administration of ImmAct yielded a robust antitumor immune response, offering protection against micrometastases and relapse.
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Affiliation(s)
- Romano Josi
- Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland (M.O.M.)
- Department of Rheumatology and Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, 3012 Bern, Switzerland
| | - Anete Ogrina
- Plant Virology Laboratory, Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia (I.B.)
| | - Dominik Rothen
- Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland (M.O.M.)
- Department of Rheumatology and Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, 3012 Bern, Switzerland
| | - Ina Balke
- Plant Virology Laboratory, Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia (I.B.)
| | - Arnau Solé Casaramona
- Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland (M.O.M.)
- Department of Rheumatology and Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland
- Graduate School for Cellular and Biomedical Sciences (GCB), University of Bern, 3012 Bern, Switzerland
| | - Simone de Brot
- COMPATH, Institute of Animal Pathology, University of Bern, 3012 Bern, Switzerland;
| | - Mona O. Mohsen
- Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland (M.O.M.)
- Department of Rheumatology and Immunology RIA, University Hospital Bern, 3010 Bern, Switzerland
- Tajarub Research & Development, Doha P.O. Box 12627, Qatar
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26
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Mochida Y, Uchida S. mRNA vaccine designs for optimal adjuvanticity and delivery. RNA Biol 2024; 21:1-27. [PMID: 38528828 PMCID: PMC10968337 DOI: 10.1080/15476286.2024.2333123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/26/2024] [Accepted: 03/15/2024] [Indexed: 03/27/2024] Open
Abstract
Adjuvanticity and delivery are crucial facets of mRNA vaccine design. In modern mRNA vaccines, adjuvant functions are integrated into mRNA vaccine nanoparticles, allowing the co-delivery of antigen mRNA and adjuvants in a unified, all-in-one formulation. In this formulation, many mRNA vaccines utilize the immunostimulating properties of mRNA and vaccine carrier components, including lipids and polymers, as adjuvants. However, careful design is necessary, as excessive adjuvanticity and activation of improper innate immune signalling can conversely hinder vaccination efficacy and trigger adverse effects. mRNA vaccines also require delivery systems to achieve antigen expression in antigen-presenting cells (APCs) within lymphoid organs. Some vaccines directly target APCs in the lymphoid organs, while others rely on APCs migration to the draining lymph nodes after taking up mRNA vaccines. This review explores the current mechanistic understanding of these processes and the ongoing efforts to improve vaccine safety and efficacy based on this understanding.
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Affiliation(s)
- Yuki Mochida
- Department of Advanced Nanomedical Engineering, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kawasaki, Japan
| | - Satoshi Uchida
- Department of Advanced Nanomedical Engineering, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Innovation Center of NanoMedicine (iCONM), Kawasaki Institute of Industrial Promotion, Kawasaki, Japan
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27
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Kramps T. Introduction to RNA Vaccines Post COVID-19. Methods Mol Biol 2024; 2786:1-22. [PMID: 38814388 DOI: 10.1007/978-1-0716-3770-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
Available prophylactic vaccines help prevent many infectious diseases that burden humanity. Future vaccinology will likely extend these benefits by more effectively countering newly emerging pathogens, fighting currently intractable infections, or even generating novel treatment modalities for non-infectious diseases. Instead of applying protein antigen directly, RNA vaccines contain short-lived genetic information that guides the expression of protein antigen in the vaccinee, like infection with a recombinant viral vector. Upon decades of research, messenger RNA-lipid nanoparticle (mRNA-LNP) vaccines have proven clinical value in addressing the COVID-19 pandemic as they combine benefits of killed subunit vaccines and live-attenuated vectors, including flexible production, self-adjuvanting effects, and stimulation of humoral and cellular immunity. RNA vaccines remain subject to continued development raising high hopes for broader future application. Their mechanistic versatility promises to make them a key tool of vaccinology and immunotherapy going forward. Here, I briefly review key developments in RNA vaccines and outline the contents of this volume of Methods in Molecular Biology.
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28
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Chandarana C, Tiwari A. A Review of Clinical Trials of Cancer and Its Treatment as a Vaccine. Rev Recent Clin Trials 2024; 19:7-33. [PMID: 37953617 DOI: 10.2174/0115748871260733231031081921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 08/20/2023] [Accepted: 09/11/2023] [Indexed: 11/14/2023]
Abstract
BACKGROUND Cancer and infectious diseases are one of the greatest challenges of modern medicine. An unhealthy lifestyle, poor drug use, or drug misuse contribute to the rise in morbidity and mortality brought on by these illnesses. The inadequacies of the medications now being used to treat these disorders, along with the growing issue of drug resistance, have compelled researchers to look for novel compounds with therapeutic promise. The number of infections and diseases has significantly abated due to vaccine development and use over time, which is described in detail. Several novel vaccines can now be produced by manipulating Deoxyribonucleic acid (DNA), Ribonucleic acid (RNA), Messenger Ribonucleic acid (mRNA), proteins, viral vector Recombinant, and other molecules due to advances in genetic engineering and our understanding of the immune defense. OBJECTIVE The main topic of discussion is cancer-based vaccinations, which were developed less than a decade ago but have already been used to treat a wide range of both life-threatening and deadly diseases. It contains clinical studies for cancer vaccines against kidney, liver, prostate, cervix, and certain RNA-based cancer vaccines against breast and bladder cancer. RESULTS Numerous studies using various DNA and RNA-based methods have been conducted on the basis of cancer, with 9-10 diseases related to DNA and 8-9 diseases associated with RNA. Some of these studies have been completed, while others have been eliminated due to a lack of research; further studies are ongoing regarding the same. CONCLUSION This brief discussion of vaccines and their varieties with examples also discusses vaccine clinical trials in relation to cancer diseases in this DNA and RNA-based cancer vaccine that has had successful clinical trials like the cervical cancer drug VGX-3100, the kidney cancer drug Pembrolizumab, MGN-1601, the prostate cancer drug pTVG-HP with rhGM-CSF, the melanoma cancer drug proteasome siRNA, and the lung cancer drug FRAME-001.
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Affiliation(s)
- Chandani Chandarana
- Department of Quality Assurance, SSR College of Pharmacy, Sayli Road, Silvassa, U.T of Dadra Nagar and Haveli- 396230, India
| | - Anuradha Tiwari
- Department of Quality Assurance, SSR College of Pharmacy, Sayli Road, Silvassa, U.T of Dadra Nagar and Haveli- 396230, India
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Rauch S, Lutz J, Mühe J, Kowalczyk A, Schlake T, Heidenreich R. Sequence-Optimized mRNA Vaccines Against Infectious Disease. Methods Mol Biol 2024; 2786:183-203. [PMID: 38814395 DOI: 10.1007/978-1-0716-3770-8_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
Developing effective mRNA vaccines poses certain challenges concerning mRNA stability and ability to induce sufficient immune stimulation and requires a specific panel of techniques for production and testing. Here, we describe the production of stabilized mRNA vaccines (RNActive® technology) with enhanced immunogenicity, generated using conventional nucleotides only, by introducing changes to the mRNA sequence and by formulation into lipid nanoparticles. Methods described here include the synthesis, purification, and formulation of mRNA vaccines as well as a comprehensive panel of in vitro and in vivo methods for evaluation of vaccine quality and immunogenicity.
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30
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Hasan M, Khatun A, Kogure K. Intradermal Delivery of Naked mRNA Vaccines via Iontophoresis. Pharmaceutics 2023; 15:2678. [PMID: 38140019 PMCID: PMC10747697 DOI: 10.3390/pharmaceutics15122678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Revised: 11/17/2023] [Accepted: 11/23/2023] [Indexed: 12/24/2023] Open
Abstract
Messenger RNA (mRNA) vaccines against infectious diseases and for anticancer immunotherapy have garnered considerable attention. Currently, mRNA vaccines encapsulated in lipid nanoparticles are administrated via intramuscular injection using a needle. However, such administration is associated with pain, needle phobia, and lack of patient compliance. Furthermore, side effects such as fever and anaphylaxis associated with the lipid nanoparticle components are also serious problems. Therefore, noninvasive, painless administration of mRNA vaccines that do not contain other problematic components is highly desirable. Antigen-presenting cells reside in the epidermis and dermis, making the skin an attractive vaccination site. Iontophoresis (ItP) uses weak electric current applied to the skin surface and offers a noninvasive permeation technology that enables intradermal delivery of hydrophilic and ionic substances. ItP-mediated intradermal delivery of biological macromolecules has also been studied. Herein, we review the literature on the use of ItP technology for intradermal delivery of naked mRNA vaccines which is expected to overcome the challenges associated with mRNA vaccination. In addition to the physical mechanism, we discuss novel biological mechanisms of iontophoresis, particularly ItP-mediated opening of the skin barriers and the intracellular uptake pathway, and how the combined mechanisms can allow for effective intradermal delivery of mRNA vaccines.
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Affiliation(s)
- Mahadi Hasan
- Department of Animal Disease Model, Research Center for Experimental Modeling Human Disease, Kanazawa University, Kanazawa 920-8640, Japan; (M.H.); (A.K.)
| | - Anowara Khatun
- Department of Animal Disease Model, Research Center for Experimental Modeling Human Disease, Kanazawa University, Kanazawa 920-8640, Japan; (M.H.); (A.K.)
| | - Kentaro Kogure
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan
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31
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Chen G, Kong D, Lin Y. Neo-Antigen-Reactive T Cells Immunotherapy for Colorectal Cancer: A More Personalized Cancer Therapy Approach. GLOBAL CHALLENGES (HOBOKEN, NJ) 2023; 7:2200186. [PMID: 37970536 PMCID: PMC10632666 DOI: 10.1002/gch2.202200186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 05/09/2023] [Indexed: 11/17/2023]
Abstract
Colorectal cancer (CRC) is the second most common malignancy in women and the third most frequent cancer in men. Evidence has revealed that the survival of patients with metastatic CRC is very low, between one and three years. Neoantigens are known proteins encoded by mutations in tumor cells. It is theorized that recognizing neoantigens by T cells leads to T cell activation and further antitumor responses. Neoantigen-reactive T cells (NRTs) are designed against the mentioned neoantigens expressed by tumor cells. NRTs selectively kill tumor cells without damage to non-cancerous cells. Identifying patient-specific and high immunogen neoantigens is important in NRT immunotherapy of patients with CRC. However, the main challenges are the side effects and preparation of NRTs, as well as the effectiveness of these cells in vivo. This review summarized the properties of neoantigens as well as the preparation and therapeutic outcomes of NRTs for the treatment of CRC.
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Affiliation(s)
- Guan‐Liang Chen
- Department of Gastroenterology SurgeryAffiliated Hospital of Shaoxing UniversityShaoxing312000China
| | - De‐Xia Kong
- Center for General Practice MedicineDepartment of GastroenterologyZhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeNo. 158 Shangtang RoadHangzhouZhejiang310014China
| | - Yan Lin
- Center for General Practice MedicineDepartment of GastroenterologyZhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical CollegeNo. 158 Shangtang RoadHangzhouZhejiang310014China
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32
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Yu MZ, Wang NN, Zhu JQ, Lin YX. The clinical progress and challenges of mRNA vaccines. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023; 15:e1894. [PMID: 37096256 DOI: 10.1002/wnan.1894] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 04/26/2023]
Abstract
Owing to the breakthroughs in the prevention and control of the COVID-19 pandemic, messenger RNA (mRNA)-based vaccines have emerged as promising alternatives to conventional vaccine approaches for infectious disease prevention and anticancer treatments. Advantages of mRNA vaccines include flexibility in designing and manipulating antigens of interest, scalability in rapid response to new variants, ability to induce both humoral and cell-mediated immune responses, and ease of industrialization. This review article presents the latest advances and innovations in mRNA-based vaccines and their clinical translations in the prevention and treatment of infectious diseases or cancers. We also highlight various nanoparticle delivery platforms that contribute to their success in clinical translation. Current challenges related to mRNA immunogenicity, stability, and in vivo delivery and the strategies for addressing them are also discussed. Finally, we provide our perspectives on future considerations and opportunities for applying mRNA vaccines to fight against major infectious diseases and cancers. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Lipid-Based Structures.
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Affiliation(s)
- Meng-Zhen Yu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, People's Republic of China
- University of Chinese Academy of Sciences (UCAS), Beijing, People's Republic of China
| | - Nan-Nan Wang
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, People's Republic of China
- University of Chinese Academy of Sciences (UCAS), Beijing, People's Republic of China
| | - Jia-Qing Zhu
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, People's Republic of China
| | - Yao-Xin Lin
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, People's Republic of China
- University of Chinese Academy of Sciences (UCAS), Beijing, People's Republic of China
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Prakash S. mRNA-Based Nanomedicine: A New Strategy for Treating Infectious Diseases and Beyond. Eur J Drug Metab Pharmacokinet 2023; 48:515-529. [PMID: 37656402 DOI: 10.1007/s13318-023-00849-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/03/2023] [Indexed: 09/02/2023]
Abstract
Messenger RNA (mRNA) has emerged as a new therapeutic agent for the prevention and treatment of a wide range of diseases. The recent achievement of the two lipid nanoparticle-mRNA vaccines developed by Moderna and Pfizer-BioNTech against coronavirus 2019 (COVID-19) disease in record time highlights the huge potential of mRNA technology and reshaping the landscape of vaccine development and the future of gene therapies. Challenges related to translational efficacy, mRNA stability, immunogenicity, and ensuring the quality of final products have been significantly improved by recent advancements in mRNA engineering and delivery. Thus, the present review aims to provide the latest innovations that incrementally overcome these issues and future directions in the context of ongoing clinical trials against infectious diseases and beyond.
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Affiliation(s)
- Satyendra Prakash
- Centre of Biotechnology, Faculty of Science, University of Allahabad, Allahabad, India.
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34
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Jiang XT, Liu Q. mRNA vaccination in breast cancer: current progress and future direction. J Cancer Res Clin Oncol 2023; 149:9435-9450. [PMID: 37100972 PMCID: PMC10132791 DOI: 10.1007/s00432-023-04805-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Accepted: 04/19/2023] [Indexed: 04/28/2023]
Abstract
Messenger RNA (mRNA) vaccination has proven to be highly successful in combating Coronavirus disease 2019 (COVID-19) and has recently sparked tremendous interest. This technology has been a popular topic of research over the past decade and is viewed as a promising treatment strategy for cancer immunotherapy. However, despite being the most prevalent malignant disease for women worldwide, breast cancer patients have limited access to immunotherapy benefits. mRNA vaccination has the potential to convert cold breast cancer into hot and expand the responders. Effective mRNA vaccine design for in vivo function requires consideration of vaccine targets, mRNA structures, transport vectors, and injection routes. This review provides an overview of pre-clinical and clinical data on various mRNA vaccination platforms used for breast cancer treatment and discusses potential approaches to combine appropriate vaccination platforms or other immunotherapies to improve mRNA vaccine therapy efficacy for breast cancer.
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Affiliation(s)
- Xiao-Ting Jiang
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, China
| | - Qiang Liu
- Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, 107 Yanjiang West Road, Guangzhou, 510120, China.
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35
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Sun B, Wu W, Narasipura EA, Ma Y, Yu C, Fenton OS, Song H. Engineering nanoparticle toolkits for mRNA delivery. Adv Drug Deliv Rev 2023; 200:115042. [PMID: 37536506 DOI: 10.1016/j.addr.2023.115042] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 07/26/2023] [Accepted: 07/31/2023] [Indexed: 08/05/2023]
Abstract
The concept of using mRNA to produce its own medicine in situ in the body makes it an ideal drug candidate, holding great potential to revolutionize the way we approach medicine. The unique characteristics of mRNA, as well as its customizable biomedical functions, call for the rational design of delivery systems to protect and transport mRNA molecules. In this review, a nanoparticle toolkit is presented for the development of mRNA-based therapeutics from a drug delivery perspective. Nano-delivery systems derived from either natural systems or chemical synthesis, in the nature of organic or inorganic materials, are summarised. Delivery strategies in controlling the tissue targeting and mRNA release, as well as the role of nanoparticles in building and boosting the activity of mRNA drugs, have also been introduced. In the end, our insights into the clinical and translational development of mRNA nano-drugs are presented.
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Affiliation(s)
- Bing Sun
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, QLD 4072, Australia
| | - Weixi Wu
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, QLD 4072, Australia
| | - Eshan A Narasipura
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Yutian Ma
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Chengzhong Yu
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, QLD 4072, Australia
| | - Owen S Fenton
- Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
| | - Hao Song
- Australian Institute for Bioengineering and Nanotechnology, the University of Queensland, Brisbane, QLD 4072, Australia.
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36
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Lee KW, Yam JWP, Mao X. Dendritic Cell Vaccines: A Shift from Conventional Approach to New Generations. Cells 2023; 12:2147. [PMID: 37681880 PMCID: PMC10486560 DOI: 10.3390/cells12172147] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/21/2023] [Accepted: 08/23/2023] [Indexed: 09/09/2023] Open
Abstract
In the emerging era of cancer immunotherapy, immune checkpoint blockades (ICBs) and adoptive cell transfer therapies (ACTs) have gained significant attention. However, their therapeutic efficacies are limited due to the presence of cold type tumors, immunosuppressive tumor microenvironment, and immune-related side effects. On the other hand, dendritic cell (DC)-based vaccines have been suggested as a new cancer immunotherapy regimen that can address the limitations encountered by ICBs and ACTs. Despite the success of the first generation of DC-based vaccines, represented by the first FDA-approved DC-based therapeutic cancer vaccine Provenge, several challenges remain unsolved. Therefore, new DC vaccine strategies have been actively investigated. This review addresses the limitations of the currently most adopted classical DC vaccine and evaluates new generations of DC vaccines in detail, including biomaterial-based, immunogenic cell death-inducing, mRNA-pulsed, DC small extracellular vesicle (sEV)-based, and tumor sEV-based DC vaccines. These innovative DC vaccines are envisioned to provide a significant breakthrough in cancer immunotherapy landscape and are expected to be supported by further preclinical and clinical studies.
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Affiliation(s)
- Kyu-Won Lee
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
| | - Judy Wai Ping Yam
- Department of Pathology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong; (K.-W.L.); (J.W.P.Y.)
- State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Xiaowen Mao
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao
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37
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Yihunie W, Nibret G, Aschale Y. Recent Advances in Messenger Ribonucleic Acid (mRNA) Vaccines and Their Delivery Systems: A Review. Clin Pharmacol 2023; 15:77-98. [PMID: 37554660 PMCID: PMC10405914 DOI: 10.2147/cpaa.s418314] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 07/28/2023] [Indexed: 08/10/2023] Open
Abstract
Messenger ribonucleic acid (mRNA) was found as the intermediary that transfers genetic information from DNA to ribosomes for protein synthesis in 1961. The emergency use authorization of the two covid-19 mRNA vaccines, BNT162b2 and mRNA-1273, is a significant achievement in the history of vaccine development. Because they are generated in a cell-free environment using the in vitro transcription (IVT) process, mRNA vaccines are risk-free. Moreover, chemical modifications to the mRNA molecule, such as cap structures and changed nucleosides, have proved critical in overcoming immunogenicity concerns, achieving sustained stability, and achieving effective, accurate protein production in vivo. Several vaccine delivery strategies (including protamine, lipid nanoparticles (LNPs), polymers, nanoemulsions, and cell-based administration) were also optimized to load and transport RNA into the cytosol. LNPs, which are composed of a cationic or a pH-dependent ionizable lipid layer, a polyethylene glycol (PEG) component, phospholipids, and cholesterol, are the most advanced systems for delivering mRNA vaccines. Moreover, modifications of the four components that make up the LNPs showed to increase vaccine effectiveness and reduce side effects. Furthermore, the introduction of biodegradable lipids improved LNP biocompatibility. Furthermore, mRNA-based therapies are expected to be effective treatments for a variety of refractory conditions, including infectious diseases, metabolic genetic diseases, cancer, cardiovascular and cerebrovascular diseases. Therefore, the present review aims to provide the scientific community with up-to-date information on mRNA vaccines and their delivery systems.
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Affiliation(s)
- Wubetu Yihunie
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Getinet Nibret
- Department of Pharmacy, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
| | - Yibeltal Aschale
- Department of Medical Laboratory Science, College of Health Sciences, Debre Markos University, Debre Markos, Ethiopia
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38
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Rechberger JS, Toll SA, Vanbilloen WJF, Daniels DJ, Khatua S. Exploring the Molecular Complexity of Medulloblastoma: Implications for Diagnosis and Treatment. Diagnostics (Basel) 2023; 13:2398. [PMID: 37510143 PMCID: PMC10378552 DOI: 10.3390/diagnostics13142398] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Medulloblastoma is the most common malignant brain tumor in children. Over the last few decades, significant progress has been made in revealing the key molecular underpinnings of this disease, leading to the identification of distinct molecular subgroups with different clinical outcomes. In this review, we provide an update on the molecular landscape of medulloblastoma and treatment strategies. We discuss the four main molecular subgroups (WNT-activated, SHH-activated, and non-WNT/non-SHH groups 3 and 4), highlighting the key genetic alterations and signaling pathways associated with each entity. Furthermore, we explore the emerging role of epigenetic regulation in medulloblastoma and the mechanism of resistance to therapy. We also delve into the latest developments in targeted therapies and immunotherapies. Continuing collaborative efforts are needed to further unravel the complex molecular mechanisms and profile optimal treatment for this devastating disease.
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Affiliation(s)
- Julian S Rechberger
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Stephanie A Toll
- Department of Pediatrics, Division of Hematology/Oncology, Children's Hospital of Michigan, Detroit, MI 48201, USA
| | - Wouter J F Vanbilloen
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Neurology, Elisabeth-Tweesteden Hospital, 5022 Tilburg, The Netherlands
| | - David J Daniels
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Soumen Khatua
- Department of Pediatric Hematology/Oncology, Section of Neuro-Oncology, Mayo Clinic, Rochester, MN 55905, USA
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39
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Pascolo S. Nonreplicating synthetic mRNA vaccines: A journey through the European (Journal of Immunology) history. Eur J Immunol 2023; 53:e2249941. [PMID: 37029096 DOI: 10.1002/eji.202249941] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/29/2023] [Accepted: 04/03/2023] [Indexed: 04/09/2023]
Abstract
The first worldwide article reporting that injections of synthetic nonreplicating mRNA could be used as a vaccine, which originated from a French team located in Paris, was published in the European Journal of Immunology (EJI) in 1993. It relied on work conducted by several research groups in a handful of countries since the 1960s, which put forward the precise description of eukaryotic mRNA and the method to reproduce this molecule in vitro as well as how to transfect it into mammalian cells. Thereafter, the first industrial development of this technology began in Germany in 2000, with the founding of CureVac, which stemmed from another description of a synthetic mRNA vaccine published in EJI in 2000. The first clinical studies investigating mRNA vaccines in humans were performed as collaboration between CureVac and the University of Tübingen in Germany as early as 2003. Finally, the first worldwide approved mRNA vaccine (an anti-COVID-19 vaccine) is based on the mRNA technologies developed by BioNTech since its 2008 foundation in Mainz, Germany, and earlier by the pioneering academic work of its founders. In addition to the past, present, and future of mRNA-based vaccines, the article aims to present the geographical distribution of the early work, how the development of the technology was implemented by several independent and internationally distributed research teams, as well as the controversies on the optimal way to design or formulate and administer mRNA vaccines.
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Affiliation(s)
- Steve Pascolo
- Department of Dermatology, University Hospital Zürich (USZ), University of Zürich (UZH), Zürich, Switzerland
- Faculty of Medicine, University of Zürich, Zürich, Switzerland
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40
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Mishra R, Sukhbaatar A, Mori S, Kodama T. Metastatic lymph node targeted CTLA4 blockade: a potent intervention for local and distant metastases with minimal ICI-induced pneumonia. J Exp Clin Cancer Res 2023; 42:132. [PMID: 37259163 DOI: 10.1186/s13046-023-02645-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/14/2023] [Indexed: 06/02/2023] Open
Abstract
BACKGROUND Immune checkpoint blockade (ICB) elicits a strong and durable therapeutic response, but its application is limited by disparate responses and its associated immune-related adverse events (irAEs). Previously, in a murine model of lymph node (LN) metastasis, we showed that intranodal administration of chemotherapeutic agents using a lymphatic drug delivery system (LDDS) elicits stronger therapeutic responses in comparison to systemic drug delivery approaches, while minimizing systemic toxicity, due to its improved pharmacokinetic profile at the intended site. Importantly, the LN is a reservoir of immunotherapeutic targets. We therefore hypothesized that metastatic LN-targeted ICB can amplify anti-tumor response and uncouple it from ICB-induced irAEs. METHODS To test our hypothesis, models of LN and distant metastases were established with luciferase expressing LM8 cells in MXH10/Mo-lpr/lpr mice, a recombinant inbred strain of mice capable of recapitulating ICB-induced interstitial pneumonia. This model was used to interrogate ICB-associated therapeutic response and immune related adverse events (irAEs) by in vivo imaging, high-frequency ultrasound imaging and histopathology. qPCR and flowcytometry were utilized to uncover the mediators of anti-tumor immunity. RESULTS Tumor-bearing LN (tbLN)-directed CTLA4 blockade generated robust anti-tumor response against local and systemic metastases, thereby improving survival. The anti-tumor effects were accompanied by an upregulation of effector CD8T cells in the tumor-microenvironment and periphery. In comparison, non-specific CTLA4 blockade was found to elicit weaker anti-tumor effect and exacerbated ICI-induced irAEs, especially interstitial pneumonia. Together these data highlight the importance of tbLN-targeted checkpoint blockade for efficacious response. CONCLUSIONS Intranodal delivery of immune checkpoint inhibitors to metastatic LN can potentiate therapeutic response while minimizing irAEs stemming from systemic lowering of immune activation threshold.
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Affiliation(s)
- Radhika Mishra
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
| | - Ariunbuyan Sukhbaatar
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Division of Oral and Maxillofacial Oncology and Surgical Sciences, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
| | - Shiro Mori
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
- Division of Oral and Maxillofacial Oncology and Surgical Sciences, Graduate School of Dentistry, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan
| | - Tetsuya Kodama
- Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.
- Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Miyagi, 980-8575, Japan.
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Hoffmann M, Gerlach S, Takamiya M, Tarazi S, Hersch N, Csiszár A, Springer R, Dreissen G, Scharr H, Rastegar S, Beil T, Strähle U, Merkel R, Hoffmann B. Smuggling on the Nanoscale-Fusogenic Liposomes Enable Efficient RNA-Transfer with Negligible Immune Response In Vitro and In Vivo. Pharmaceutics 2023; 15:pharmaceutics15041210. [PMID: 37111695 PMCID: PMC10146161 DOI: 10.3390/pharmaceutics15041210] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 04/04/2023] [Accepted: 04/05/2023] [Indexed: 04/29/2023] Open
Abstract
The efficient and biocompatible transfer of nucleic acids into mammalian cells for research applications or medical purposes is a long-standing, challenging task. Viral transduction is the most efficient transfer system, but often entails high safety levels for research and potential health impairments for patients in medical applications. Lipo- or polyplexes are commonly used transfer systems but result in comparably low transfer efficiencies. Moreover, inflammatory responses caused by cytotoxic side effects were reported for these transfer methods. Often accountable for these effects are various recognition mechanisms for transferred nucleic acids. Using commercially available fusogenic liposomes (Fuse-It-mRNA), we established highly efficient and fully biocompatible transfer of RNA molecules for in vitro as well as in vivo applications. We demonstrated bypassing of endosomal uptake routes and, therefore, of pattern recognition receptors that recognize nucleic acids with high efficiency. This may underlie the observed almost complete abolishment of inflammatory cytokine responses. RNA transfer experiments into zebrafish embryos and adult animals fully confirmed the functional mechanism and the wide range of applications from single cells to organisms.
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Affiliation(s)
- Marco Hoffmann
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Sven Gerlach
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Masanari Takamiya
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany
| | - Samar Tarazi
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Nils Hersch
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Agnes Csiszár
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Ronald Springer
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Georg Dreissen
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Hanno Scharr
- IAS-8: Data Analytics and Machine Learning, Institute for Advanced Simulation, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Sepand Rastegar
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany
| | - Tanja Beil
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany
| | - Uwe Strähle
- Institute of Biological and Chemical Systems-Biological Information Processing (IBCS-BIP), Karlsruhe Institute of Technology (KIT), Postfach 3640, 76021 Karlsruhe, Germany
| | - Rudolf Merkel
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
| | - Bernd Hoffmann
- IBI-2: Mechanobiology, Institute of Biological Information Processing, Forschungszentrum Jülich, 52428 Jülich, Germany
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42
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Mendez-Gomez HR, DeVries A, Castillo P, Stover BD, Qdaisat S, Von Roemeling C, Ogando-Rivas E, Weidert F, McGuiness J, Zhang D, Chung MC, Li D, Zhang C, Marconi C, Campaneria Y, Chardon-Robles J, Grippin A, Karachi A, Thomas N, Huang J, Milner R, Sahay B, Sawyer WG, Ligon JA, Silver N, Simon E, Cleaver B, Wynne K, Hodik M, Molinaro A, Guan J, Kellish P, Doty A, Lee JH, Carrera-Justiz S, Rahman M, Gatica S, Mueller S, Prados M, Ghiaseddin A, Mitchell DA, Sayour EJ. mRNA aggregates harness danger response for potent cancer immunotherapy. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2023:2023.03.12.23287108. [PMID: 36993772 PMCID: PMC10055442 DOI: 10.1101/2023.03.12.23287108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/06/2023]
Abstract
Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of 'onion-like' multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.
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43
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Lu L, Ma W, Johnson CH, Khan SA, Irwin ML, Pusztai L. In silico designed mRNA vaccines targeting CA-125 neoantigen in breast and ovarian cancer. Vaccine 2023; 41:2073-2083. [PMID: 36813666 PMCID: PMC10064809 DOI: 10.1016/j.vaccine.2023.02.048] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 02/12/2023] [Accepted: 02/14/2023] [Indexed: 02/22/2023]
Abstract
Somatic mutation-derived neoantigens are associated with patient survival in breast and ovarian cancer. These neoantigens are targets for cancer, as shown by the implementation of neoepitope peptides as cancer vaccines. The success of cost-effective multi-epitope mRNA vaccines against SARS-Cov-2 in the pandemic established a model for reverse vaccinology. In this study, we aimed to develop an in silico pipeline designing an mRNA vaccine of the CA-125 neoantigen against breast and ovarian cancer, respectively. Using immuno-bioinformatics tools, we predicted cytotoxic CD8+ T cell epitopes based on somatic mutation-driven neoantigens of CA-125 in breast or ovarian cancer, constructed a self-adjuvant mRNA vaccine with CD40L and MHC-I -targeting domain to enhance cross-presentation of neoepitopes by dendritic cells. With an in silico ImmSim algorithm, we estimated the immune responses post-immunization, showing IFN-γ and CD8+ T cell response. The strategy described in this study may be scaled up and implemented to design precision multi-epitope mRNA vaccines by targeting multiple neoantigens.
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Affiliation(s)
- Lingeng Lu
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT 06510, USA; Yale Cancer Center, Yale University, New Haven, CT 06510, USA.
| | - Wenxue Ma
- Department of Medicine, Moores Cancer Center and Sanford Stem Cell Clinical Center, University of California San Diego, La Jolla, CA 92093, USA
| | - Caroline H Johnson
- Yale Cancer Center, Yale University, New Haven, CT 06510, USA; Department of Environmental Health Science, Yale School of Public Health, Yale University, New Haven, CT 06510, USA
| | - Sajid A Khan
- Yale Cancer Center, Yale University, New Haven, CT 06510, USA; Department of Surgery, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
| | - Melinda L Irwin
- Department of Chronic Disease Epidemiology, Yale School of Public Health, Yale University, New Haven, CT 06510, USA; Yale Cancer Center, Yale University, New Haven, CT 06510, USA
| | - Lajos Pusztai
- Yale Cancer Center, Yale University, New Haven, CT 06510, USA; Department of Medical Oncology, Yale School of Medicine, Yale University, New Haven, CT 06510, USA
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44
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Wang Z, Ma W, Fu X, Qi Y, Zhao Y, Zhang S. Development and applications of mRNA treatment based on lipid nanoparticles. Biotechnol Adv 2023; 65:108130. [PMID: 36933868 DOI: 10.1016/j.biotechadv.2023.108130] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 12/06/2022] [Accepted: 03/13/2023] [Indexed: 03/18/2023]
Abstract
Nucleic acid-based therapies such as messenger RNA have the potential to revolutionize modern medicine and enhance the performance of existing pharmaceuticals. The key challenges of mRNA-based therapies are delivering the mRNA safely and effectively to the target tissues and cells and controlling its release from the delivery vehicle. Lipid nanoparticles (LNPs) have been widely studied as drug carriers and are considered to be state-of-the-art technology for nucleic acid delivery. In this review, we begin by presenting the advantages and mechanisms of action of mRNA therapeutics. Then we discuss the design of LNP platforms based on ionizable lipids and the applications of mRNA-LNP vaccines for prevention of infectious diseases and for treatment of cancer and various genetic diseases. Finally, we describe the challenges and future prospects of mRNA-LNP therapeutics.
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Affiliation(s)
- Zhe Wang
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Wanting Ma
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Xingxing Fu
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Yanfei Qi
- Centenary Institute, The University of Sydney, Sydney, NSW 2050, Australia
| | - Yinan Zhao
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China
| | - Shubiao Zhang
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian 116600, China.
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45
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Sun H, Zhang Y, Wang G, Yang W, Xu Y. mRNA-Based Therapeutics in Cancer Treatment. Pharmaceutics 2023; 15:pharmaceutics15020622. [PMID: 36839944 PMCID: PMC9964383 DOI: 10.3390/pharmaceutics15020622] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 01/28/2023] [Accepted: 01/28/2023] [Indexed: 02/15/2023] Open
Abstract
Over the past two decades, significant technological innovations have led to messenger RNA (mRNA) becoming a promising option for developing prophylactic and therapeutic vaccines, protein replacement therapies, and genome engineering. The success of the two COVID-19 mRNA vaccines has sparked new enthusiasm for other medical applications, particularly in cancer treatment. In vitro-transcribed (IVT) mRNAs are structurally designed to resemble naturally occurring mature mRNA. Delivery of IVT mRNA via delivery platforms such as lipid nanoparticles allows host cells to produce many copies of encoded proteins, which can serve as antigens to stimulate immune responses or as additional beneficial proteins for supplements. mRNA-based cancer therapeutics include mRNA cancer vaccines, mRNA encoding cytokines, chimeric antigen receptors, tumor suppressors, and other combination therapies. To better understand the current development and research status of mRNA therapies for cancer treatment, this review focused on the molecular design, delivery systems, and clinical indications of mRNA therapies in cancer.
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Affiliation(s)
- Han Sun
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yu Zhang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ge Wang
- Department of Oral Maxillofacial & Head and Neck Oncology, National Center of Stomatology, National Clinical Research Center for Oral Disease, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
| | - Wen Yang
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yingjie Xu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
- Correspondence:
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46
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Lipid nanoparticles technology in vaccines: Shaping the future of prophylactic medicine. Colloids Surf B Biointerfaces 2023; 222:113111. [PMID: 36586237 DOI: 10.1016/j.colsurfb.2022.113111] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/07/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
Throughout decades, the intrinsic power of the immune system to fight pathogens has inspired researchers to develop techniques that enable the prevention or treatment of infections via boosting the immune response against the target pathogens, which has led to the evolution of vaccines. The recruitment of Lipid nanoparticles (LNPs) as either vaccine delivery platforms or immunogenic modalities has witnessed a breakthrough recently, which has been crowned with the development of effective LNPs-based vaccines against COVID-19. In the current article, we discuss some principles of such a technology, with a special focus on the technical aspects from a translational perspective. Representative examples of LNPs-based vaccines against cancer, COVID-19, as well as other infectious diseases, autoimmune diseases, and allergies are highlighted, considering the challenges and promises. Lastly, the key features that can improve the clinical translation of this area of endeavor are inspired.
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47
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Vavilis T, Stamoula E, Ainatzoglou A, Sachinidis A, Lamprinou M, Dardalas I, Vizirianakis IS. mRNA in the Context of Protein Replacement Therapy. Pharmaceutics 2023; 15:pharmaceutics15010166. [PMID: 36678793 PMCID: PMC9866414 DOI: 10.3390/pharmaceutics15010166] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/22/2022] [Accepted: 12/29/2022] [Indexed: 01/06/2023] Open
Abstract
Protein replacement therapy is an umbrella term used for medical treatments that aim to substitute or replenish specific protein deficiencies that result either from the protein being absent or non-functional due to mutations in affected patients. Traditionally, such an approach requires a well characterized but arduous and expensive protein production procedure that employs in vitro expression and translation of the pharmaceutical protein in host cells, followed by extensive purification steps. In the wake of the SARS-CoV-2 pandemic, mRNA-based pharmaceuticals were recruited to achieve rapid in vivo production of antigens, proving that the in vivo translation of exogenously administered mRNA is nowadays a viable therapeutic option. In addition, the urgency of the situation and worldwide demand for mRNA-based medicine has led to an evolution in relevant technologies, such as in vitro transcription and nanolipid carriers. In this review, we present preclinical and clinical applications of mRNA as a tool for protein replacement therapy, alongside with information pertaining to the manufacture of modified mRNA through in vitro transcription, carriers employed for its intracellular delivery and critical quality attributes pertaining to the finished product.
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Affiliation(s)
- Theofanis Vavilis
- Laboratory of Biology and Genetics, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- Department of Dentistry, European University Cyprus, Nicosia 2404, Cyprus
- Correspondence:
| | - Eleni Stamoula
- Centre of Systems Biology, Department of Biotechnology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
- Department of Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Alexandra Ainatzoglou
- Centre of Systems Biology, Department of Biotechnology, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
- Department of Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Athanasios Sachinidis
- 4th Department of Internal Medicine, Hippokration General Hospital, School of Medicine, Aristotle University of Thessaloniki, 54642 Thessaloniki, Greece
| | - Malamatenia Lamprinou
- Department of Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Ioannis Dardalas
- Department of Clinical Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Ioannis S. Vizirianakis
- Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- Department of Life & Health Sciences, School of Sciences and Engineering, University of Nicosia, Nicosia 1700, Cyprus
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48
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Chen J, Zhang T, Lu Y, Yang X, Ouyang Z. Emerging trends of research on mRNA vaccines: A co-citation analysis. Hum Vaccin Immunother 2022; 18:2110409. [PMID: 36018287 DOI: 10.1080/21645515.2022.2110409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
This study was designed to evaluate the emerging trends of research on mRNA vaccines. Altogether 3056 research articles related to mRNA vaccines published since 2010 were retrieved from the Web of Science database, based on which a co-citation analysis was conducted using CiteSpace. A total of 12 clusters were derived, all of which were classified into three periods according to the content and publication time of articles: (1) The preliminary exploratory period before early 2010s, when the potential of mRNA to induce immune response was evaluated; (2) the growing up period from early 2010s to 2019, when the stability and immunogenicity of mRNA vaccines were improved and the clinical development of products were pushed forward; (3) the rapid maturity period after the outbreak of COVID-19, when two products for COVID-19 were authorized for the first time. The approval of COVID-19 vaccines is an encouraging start, while the enormous potential of mRNA vaccines remains to be explored. Future research on mRNA-based infectious disease vaccines will focus on further optimizing mRNA modification and delivery, solving problems of the approved vaccines in real world, investigating mRNA vaccines for other infectious indications, and developing self-amplifying or thermostable vaccines. Future research on mRNA-based therapeutic cancer vaccines will focus on screening proper neoantigens, enhancing the delivery of mRNA into antigen-presenting cells and overcoming suppressive tumor microenvironment.
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Affiliation(s)
- Juan Chen
- Institute of Medical Information/Medical Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ting Zhang
- Institute of Medical Information/Medical Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Yan Lu
- Institute of Medical Information/Medical Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiaoyi Yang
- Institute of Medical Information/Medical Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Zhaolian Ouyang
- Institute of Medical Information/Medical Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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49
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Bottlenecks and opportunities in immunotherapy for glioma: a narrative review. JOURNAL OF BIO-X RESEARCH 2022. [DOI: 10.1097/jbr.0000000000000135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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50
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Tian Y, Deng Z, Yang P. mRNA vaccines: A novel weapon to control infectious diseases. Front Microbiol 2022; 13:1008684. [PMID: 36267192 PMCID: PMC9576954 DOI: 10.3389/fmicb.2022.1008684] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/06/2022] [Indexed: 12/01/2022] Open
Abstract
Infectious diseases have always threatened human life, but with the development of vaccines, effective strategies for preventing and controlling these diseases have become available. The global outbreak of COVID-19 ushered in the advent of mRNA vaccine technologies, which quickly led to the introduction of mRNA vaccines effective against SARS-CoV-2. The success of this approach has stimulated research into the use of mRNA vaccines in the fight against other emerging as well as remerging infectious diseases. This review examines the constructive strategies and delivery systems used in mRNA vaccines and provides an overview of current clinical trials of those vaccines in the prevention of infectious diseases. The underlying mechanisms of mRNA vaccines are also discussed, including the double-edged sword of the innate immune response. Finally, the challenges but also the potential of mRNA vaccines are considered.
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Affiliation(s)
- Yuying Tian
- Faculty of Hepato-Pancreato-Biliary Surgery, Institute of Hepatobiliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- Inner Mongolia Medical University, Hohhot, China
| | - Zhuoya Deng
- Faculty of Hepato-Pancreato-Biliary Surgery, Institute of Hepatobiliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Penghui Yang
- Faculty of Hepato-Pancreato-Biliary Surgery, Institute of Hepatobiliary Surgery, The First Medical Center, Chinese PLA General Hospital, Beijing, China
- Inner Mongolia Medical University, Hohhot, China
- *Correspondence: Penghui Yang,
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